A recent claims-based analysis linked GnRH agonists with a greater risk for incident coronary heart disease and MI.10
Using data from a large, multicenter, prospective, randomized controlled trial with long follow-up, we found that adjuvant goserelin was not associated with increased cardiovascular mortality in men with locally advanced prostate cancer. Specifically, the 9-year cardiovascular mortality rate for men treated with adjuvant goserelin was 8.4% v
11.4% for men treated without adjuvant goserelin. The lack of an apparent treatment-related detrimental effect was similarly seen after censoring patients at time of salvage GnRH agonist therapy and when using alternative definitions of cardiovascular mortality. Our results also confirmed that established cardiovascular risk factors, such as prevalent CVD and DM, are associated with increased risk of cardiovascular mortality. Within subgroups of men with highest risk, there remained no apparent treatment-related increase in cardiovascular mortality.
To the best of our knowledge, these are the first analyses using data from a large prospective study to directly address the potential relationship between GnRH agonists and cardiovascular mortality. Our results are consistent with other published reports. In a prospective randomized controlled trial (RTOG 92-02), long-term adjuvant treatment with GnRH agonists was associated with greater noncancer mortality than short-term therapy, although there seemed to be no difference when classified as cardiovascular death.5,5a
Notably, there was an imbalance between the groups, with the long-term arm having a higher rate of prevalent CVD that the short-term arm (55% v
44%, respectively). A retrospective study suggested that neoadjuvant GnRH agonist therapy in men treated for early-stage prostate cancer with prostate brachytherapy was associated with worse overall survival compared with hormone-naïve men, although cancer-specific mortality was similar.29
In that series, CVD was the single largest cause of death in both groups without any obvious discrepancy between the groups (representing 24% and 22% of overall mortality in patients who did and did not receive GnRH agonist therapy, respectively). In European Organisation for Research and Treatment of Cancer trial 30891,30
in which 985 men with localized prostate cancer not suitable for local curative treatment were treated with immediate or deferred ADT (orchiectomy or GnRH agonist), overall survival favored the immediate arm seemingly as a result of fewer noncancer deaths. Specifically, death from CVD was 17.9% in the immediate arm compared with 19.7% in the deferred arm. In a recent pooled data analysis31
of three trials using varying courses of short-term GnRH agonist therapy, it was suggested that a subset of men age 65 years or older who received 6 months of ADT experienced shorter times to fatal MIs compared with men in this age group who did not receive ADT; notably, this study did not show any difference in total number of fatal MIs (18 v
16 MIs, respectively). Furthermore, compared with our study, the analysis was limited by a lower number of events (approximately one third), shorter follow-up, short treatment duration, and lack of information on known CVD risk factors.
The absence of an apparent increase in cardiovascular mortality in our study and other trials does not exclude the possibility that GnRH agonists increase noncancer mortality. Men with prostate cancer have higher rates of noncancer death than the general population,32
and GnRH agonists may contribute to this through multiple mechanisms. In the recent claims-based Surveillance, Epidemiology, and End Results-Medicare analysis that first reported an association between GnRH agonists and incident nonfatal coronary heart disease and MI,10
the effect was modest (16% and 11% increased risk, respectively) and may not translate into an apparent increase in cardiovascular mortality. Notably, the analyses by Keating et al10
also showed a greater risk for other adverse events, including incident DM (44% increased risk), which may independently contribute to noncancer, noncardiac mortality. GnRH agonists also decrease bone mineral density33,34
and increase fracture risk in men with prostate cancer,35,36
another possible cause of death.37
In addition, GnRH agonists may lead to declines in hemoglobin,38
and anemia has been shown to be a prognostic factor for survival in men with hormone-refractory prostate cancer.39
Other adverse effects such as fatigue and psychological distress40
impact quality of life and overall frailty. Thus, GnRH agonists have the potential to impact noncancer mortality through several mechanisms.
Additional studies are necessary to assess potential effects of neoadjuvant/adjuvant GnRH agonist therapy on cardiovascular mortality in men with earlier stage prostate cancer and lower rates of cancer-specific mortality. In our population of men with locally advanced disease, there was a significant rate of prostate cancer–specific mortality (35%). Cardiovascular mortality represented approximately 20% of all deaths in our study, whereas it represents closer to 30% of all deaths in the general male population.41
Especially among men with earlier stage disease and favorable prognosis in whom the role for GnRH agonists has not been clearly defined, treatment decisions need to carefully weigh potential risks and benefits.
Our study has substantial strengths. First, it is one of few prostate cancer trials with a control arm of no hormone therapy. Second, our study was large, with 945 patients, more than 11 years of follow-up for living patients, and 117 cardiovascular deaths. Although it is possible that we could have missed a small adverse treatment effect, the clinical significance of any such small effect may be questionable. Third, although we used investigator-defined cause of death as our study outcome, our ascertainment of cardiovascular mortality seems reliable given the strong association with traditional CVD risk factors, including prevalent CVD and DM, and consistency of results using alternative definitions of cardiovascular mortality. Data were not collected on each individual investigator, and thus, controlling for each investigator was not feasible. Fourth, we had information on a number of known CVD risk factors, and importantly, rates of prevalent CVD were similar between the treatment arms. We did lack detailed information on other risk factors including hyperlipidemia and certain lifestyle factors, such as smoking, diet, and physical activity, as well as CVD severity and use of cardiac medications. It is unlikely that there would have been any imbalance between the arms with respect to these other factors, however, given the size and randomized nature of our study. Fifth, the study's follow-up requirements for both arms seem to substantially exceed routine follow-up for adult men without cancer; accordingly, the possibility that any incremental difference in intensity of oncology follow-up for administration of a GnRH agonist led to a decrease in cardiovascular mortality in arm 1 seems remote and is unlikely to have affected the outcome. Finally, we observed consistency in our results when applying alternative definitions of cardiovascular mortality, when censoring at the time of salvage GnRH agonist therapy, and when imputing missing data.
In summary, although GnRH agonists are associated with greater risk of incident coronary heart disease and MI, we found no evidence that adjuvant long-term treatment with GnRH agonists increased cardiovascular mortality in men with locally advanced prostate cancer. Additional studies are needed to assess the potential relationship between GnRH agonists and cardiovascular mortality in men with lower cancer-specific mortality.